We will investigate genetic predisposition and problems in the regulation of dysphoric emotions as risk factors for childhood- onset depression, a serious and familial affective illness. We hypothesize that disruption in the early development of emotion regulation in multiple regulatory domains (biologic/social/cognitive) is necessary for the expression of childhood depression and that it occurs within a broad genetic predisposition to depressive illness. We will study high-risk families, i.e., those containing a clinically referred child proband who had a depressive disorder by age 14, and two control groups (as appropriate): referred probands who had childhood-onset anxiety disorder and probands who were free of childhood psychiatric illness. Three unique and valuable cohorts will be merged who were ascertained (as part of separate NIMH grants) while they were youngsters, are now young adults, and have offspring. Study 1 will seek to identify genes in childhood-onset depressive illness by using a strategy that combines affected relative pair and haplotype relative risk methods, screen probands and parents for expanded trinucleotide repeats and perform a genome scan; Study 2 will examine patterning of frontal EEG, autonomic nervous system reactivity, and facial expression as markers of emotion dysregulation in probands, juvenile offspring and adult siblings, of probands; Study 3 will use observational method to explore emotion, regulation in the young, offspring of grown probands and interactions, and related parent-child interactions, and their developmental unfolding: The studies will be supported by the Administrative, Scheduling & Psychiatric Evaluation, and Data Management & Statistical Cores and external consultants. By eventually integrating results of the 3 studies, we will derive a multifaceted characterization of risk factors in depressive illness and identify processes that may be protective. Such findings will facilitate primary prevention with our target population.